The present inventors have developed a range of processes for encapsulating materials such as drugs and other biologically active materials, based on forming ceramic particles using sol-gel and related technology. These were developed for controlled release application, although other applications were also envisaged. These have been described in WO 01/62332, and in Australian patent application Nos AU 2005001738, AU 2005001915 and AU 2006000193.
These methods rely on the formation of water-in-oil emulsions, in which the encapsulant is located in the water phase. Consequently they are restricted to hydrophilic encapsulants which will partition preferentially into a dispersed water phase.
For the last decade, the encapsulation and controlled release of hydrophobic species has attracted considerable interest due to the increasing number of industrial applications using hydrophobic/lipophilic active molecules. For example, in the pharmaceutical and agricultural industries, many drugs or biocides possess hydrophobic properties. Nevertheless, the means to encapsulate and controllably release these active molecules remains a challenge for these industries. On the other hand, in food, cosmetics and personal care, encapsulation and controlled release of volatile organic compounds such as flavours and perfumes, or reactive compounds such as bleaches, is becoming a dominant trend for product improvement.
Compared with traditional organic materials, inorganic matrices and more specifically ceramics have many intrinsic advantages. In particular, they are biologically inert, intrinsically hydrophilic, and represent higher mechanical strength and thermal stability. However few inorganic delivery systems have achieved precise controlled release of the encapsulated molecules.
Double emulsions provide a means for encapsulating active materials in a delivery vehicle. These systems consist of two different interfaces that require two sets of different types of surfactants. In the case of O/W/O multiple emulsions, the first set of surfactants is preferably hydrophilic for the internal interface, while the second set of surfactants, for the external interface, is preferably hydrophobic. The composition of the double emulsion is critical since the nature and concentration of the different surfactants, along with the nature and concentration of the oil phase, will affect the stability of the double emulsion. Multiple emulsions (e.g. O/W/O) usually are prepared through a two-step process. In the first step, O1/W emulsions are prepared by dispersing the internal oil in an aqueous solution in the presence of a high HLB surfactant. The formation of an emulsion of very fine oil droplets in water is achieved by extensive energy input processes such as high shear homogenisation or ultrasonification. In the second step the O1/W emulsion is added to the external oil phase containing a low HLB surfactant. To disperse the inner phase (O1/W emulsion) in the external oil phase (O2), a magnetic stirrer is generally used. The most commonly used double emulsions are of W/O/W type, but O/W/O emulsions have been used for specific applications. Disadvantages of multiple emulsions include their intrinsic instability and the complexity of their structures, and consequently their applications have been substantially restricted despite their potential usefulness. In attempts to overcome their inherent instability, which results from the aggregation and coalescence between droplets in the inner phase, suitable combinations of emulsifiers have been used to improve the emulsion stability and reduce droplet sizes. The emulsifiers are absorbed at the surface of droplets during the formation of emulsions and prevent them from coming close enough to coalesce. Polymeric synthetic emulsifiers as well as natural macromolecules can be also used in combination with monomeric emulsifiers which have been shown to improve stability and controlled release.
By combining the advantages of the intrinsic properties of multiple emulsions with sol-gel chemistry, some hollow or porous inorganic spherical particles have been produced by sequentially introducing a catalyst and a metal alkoxide precursor in the water phase. However, very limited work has been conducted to produce spherical ceramic particles containing oil or hydrophobic species using a O/W/O multiple emulsion. This is due to the strict requirements of thermodynamically stable double emulsions i.e. very narrow domain of stability in the quaternary phase diagram (water-oil-surf1-surf2). Some work [“Preparation of Silica Particles Encapsulating Retinol Using O/W/O Multiple Emulsions”, Lee, Myung-Han; Oh, Seong-Geun; Moon, Sei-Ki; Bae, Seong-Youl, Journal of Colloid and Interface Science, 240, 83-89 (2001)] has been undertaken to improve the stability of double emulsion by introducing thickening agents such as block co-polymers but with limited success. Once the metal alkoxide is added into the outer oil phase and subsequently reacted with water, the structure and stability of double emulsion is changed due to the perturbation in the balance of osmotic pressures between the two oil phases. This inherent thermodynamic instability of the double emulsion system, commonly leads to a further disadvantage with such systems: a fast (i.e. “burst”) release of encapsulated materials into the outer oil phase.
Furthermore, the complex nature of multiple emulsions renders difficult the assessment of emulsion stability and the detection of rupture and coalescence. The main experimental technique is based on the measurement of the number and size of the multiple emulsion droplets which produces limited information on the emulsion stability because it is very difficult to determine if the internal droplets do coalesce, aggregate, or rupture. Again, introducing a significant amount of silicon precursor into the double emulsion system will increase the difficulty in monitoring the emulsion chemistry.Moreover, our inability to reproduce the preparation described by Lee et al. and the obtaining of nanoparticles instead of the microparticles described in their paper further confirm the significant instability and irreproducibility of such an approach.
There is therefore a need for a robust and versatile process for encapsulating a hydrophobic material into a particle. It would be preferable if such a process provided control over the size of the particle, and optionally also over the release rate of the hydrophobic material from the particle, as well as good encapsulation efficiency of the hydrophobic material.